Chronic ethanol consumption produces brain damage manifested by morphological, physiological, biochemical and cognitive abnormalities. Controlled studies in laboratory animals have provided convincing evidence of the specificity of ethanol in inducing these abnormalities, however neither the mechanism of ethanol toxicity nor the specific morphological or functional basis of ethanol induced cognitive deficits are known. Considerable evidence has demonstrated that chronic ethanol treatment (CET) results in significant loss of hippocampal neurons, altered dendritic structure and function of surviving neurons and loss or rearrangement of synaptic connections. Damage to the septohippocampal pathway is implicated in deficient memory and learning and this has been attributed to cholinergic deafferentation of the hippocampus, although the role of GABAergic projections has not been carefully examined. Recently it has been reported that CET produces a progressive decline in spatial memory, cholinergic function and acetylcholinesterase-positive neurons in the septal area. If confirmed, these findings represent an important link in our understanding of the morphological and functional basis for the memory deficits found in alcoholism. The proposed work will attempt to confirm and extend these results to include studies of cholinergic and GABAergic morphology and function in the septa] area and the hippocampus. We will investigate the hypothesis that the septohippocampal pathway is particularly vulnerable to CET. Since septohippocampal neurons are dependent on trophic factors for survival and maintenance of their function, we will also investigate the hypothesis that their vulnerability to CET is mediated by the suppression of neurotrophic influence. The first series of experiments will use immunohistochemical, biochemical and electrophysiological techniques to examine the effects of CET on the morphology and function of the septohippocampal pathway. Both cholinergic and GABAergic septohippocampal neurons in the septal area and their target neurons (principal cells and interneurons) in the hippocampus will be studied. The second series of experiments will test the hypothesis that the vulnerability of the septohippocampal system to CET is mediated by the suppression of neurotrophic influences. Tissue culture bioassay and ELISA methods will be used to determine if CET produces a decrease in the content or bioactivity of neurotrophic factors in the hippocampus and/or if acute ethanol exposure attenuates or blocks the action of neurotrophic factors. Immunohistochemical methods will be used to determine if CET reduces the number of septohippocampal neurons immunoreactive for neurotrophic factor receptors, thus further limiting the availability of neurotrophic influence.